Etiologic and prognostic factors in ovarian cancer remain poorly understood, although emerging evidence suggests that factors related to immune response play important roles in the development and clinical treatment of this disease. Recent evidence has revealed that a subset of T cells with immunosuppressive properties, referred to as regulatory T cells (Treg), are essential for the development and maintenance of self-tolerance. There is a very consistent body of literature that points to an important role of these Treg cells in human health. These studies have shown that lower peripheral Treg cells expression is associated with autoimmune disease, allergy, and adverse transplantation outcomes, indicating that insufficient Treg cell stimulated immune suppression might lead to the development of these auto reactive health conditions. On the other hand, elevated Treg cell expression has been consistently reported in patients with a wide variety of malignancies, suggesting that Treg cell-mediated suppression might interfere with an adequate immune response to tumor associated antigens. Our group and others also provided direct evidence linking elevated Treg cell expression to greater risk of ovarian cancer and poorer prognosis. Thus, the role of Treg cells in cancer etiology and prognosis is an area of emerging interest, as high Treg activity might a) prevent an adequate immune response at the time of cancer initiation and progression, b) prevent an adequate immune response after initial treatment of the tumor;and c) result in lower responsiveness to tumor immunotherapy. To date, we are unaware of any comprehensive epidemiological study that has focused on the role Treg cells in human cancer in general or ovarian carcinogenesis in particular. Thus, we propose to evaluate the role of Treg cell burden as well as a panel of candidate genetic polymorphisms, directly relevant to Treg cell activity, in the etiology and prognosis of ovarian cancer. We hypothesize in Aim 1 that women with ovarian cancer will have higher blood Treg cell levels than healthy controls. We also expect in Aim 2 that women with a genetically determined high activity Treg cell profile will be less effective in mounting an immune response toward tumor cells in the initiation and progression phase of ovarian carcinogenesis. We further hypothesize in Aim 3 that ovarian cancer patients with a genetically determined high activity Treg cell profile will be less effective in battling residual disease. We also seek to determine in Aim 4 if genetic variability in Treg cell function can predict Treg cell expression in ovarian tumors. We propose to utilize data and specimens from core resources at our institute and from a population-based case-control study of ovarian cancer. For Aim 1, we will newly recruit 100 ovarian cancer patients and 100 controls via our institute's Biorepository to collect fresh blood samples required for Treg cell measurements. In the case-control study we recently recruited over 900 ovarian cancer patients and 1800 community controls (Specific Aim 2) from the Buffalo, NY, Pittsburgh PA, and Cleveland, OH areas. We propose to follow-up the ovarian cancer patient group and assess relevant clinical outcomes (recurrence, survival;Specific Aim 3). We will also select 630 patients with advanced stage disease with available blood and tumor samples from our institute's Ovarian Cancer Specimen Bank (Specific Aim 4). For the laboratory analyses, we will utilize Illumina Golden Gate assays and flow-cytometry techniques for the genotype and Treg cell assessment, respectively. Our statistical and genetic analyses will be carried out by a trained geneti epidemiologist. PUBLIC HEALTH RELEVANCE: The proposed study will be the first comprehensive investigation on the role of regulatory T cells in ovarian carcinogenesis. Results from this research will contribute to our understanding on how ovarian cancer develops and progresses. Findings from this study can also lay the foundation for novel immunotherapeutic strategies for this serious disease and can identify subgroups of women who might benefit most from these new therapies.